The public health risk of marijuana smoking in adults and juveniles is not clear and further studies are indicated. Smoking marijuana can alter lymphocyte function and injection of cannabinoid substances into animals can modify the biological responsiveness of lymphocytes and macrophages. We have shown that animals injected with cannabinoids become deficient in IFN production, IL-1 production, NK cell activity and CTL function. Furthermore, the addition of THC or 11-OH-THC in vitro can affect antibody formation by lymphocytes, either enhance or suppress proliferation in response to T and B cell mitogens, uniquely affect lymphocytes from various lymphoid organs, modulate IL-2 and IFN production, suppress the killing ability of CTLs and NK cells, suppress macrophage spreading and phagocytosis, and either enhance or suppress the production of IL-1. Our results also suggest that lymphocyte function in juvenile animals is more greatly affected by THC than that of adult animals. It has been reported that marijuana can modify host resistance to infectious agents, however, the cellular basis for this attenuation is not known. We feel that our results and the results of others suggest that marijuana components reversibly modulate leukocyte function possibly by mechanisms involving membrane phospholipid/protein kinase C/arachidonic acid pathways, and that exposure of animals to marijuana can modify host resistance to infectious agents. Accordingly, we propose to examine the marijuana influence at the whole animal level and at the cellular. We will test host resistance to an opportunistic facultative intracellular bacteria (Legionella pneumophila) by animal i.v. injection with select cannabinoids followed by a challenge infection and analysis of survival rates and organ CFU dissimination. The cellular basis for the cannabinoid induced modification of host resistance will be examined in studies measuring antibody, TNF and IFN production, and macrophage bactericidal capacity. We will test the effect of select cannabinoids on freshly isolated and cloned T lymphocytes, NK cells, and macrophages. Studies will include cannabinoid effects on T cell proliferation, IL-2 production and NK cell killing, along with macrophage phagyotosis and IL-1 production. At the molecular level we will examine effects on cellular protein phosphorylation, cytoplasmic calcium concentration, membrane phospholipid metabolism, and arachidonic acid and leukotriene production. These studies will further our understanding of the marijuana influence at both the whole animal and molecular levels and also contribute to a better understanding of the cell biology of the immune response.